Mutational specificity: Spectrum of mutations in kidney,stomach, and liver from lacl transgenic mice recovered after treatment with tris(2,3-dibromopropyl)phosphate

The flame retardant tris(2,3-dibromopropyl)phosphate (TDBP), once used in cotton sleepware for children, is presently banned from commerce. It produces tumors in rodents in both a sex- and tissue-specific manner. The kidney is the main target for tumor formation in male and female rats, as well as in male mice. In contrast, tumors are formed in the liver of female animals. We have used lacl transgenic male B6C3F1 mice (Big Blue®) to examine the induction of mutation in kidney, liver, and stomach after exposure to 150 mg/kg (2 days), 300 mg/kg (4 days), and 600 mg/kg (4 days of TDBP. At the highest dose, the mutant frequency was approximately 50% above control values in the kidney (P < 0.01). A smaller increase was observed in the liver (P = 0.07), while no increase was seen in the stomach (P = 0.28). Sequence analysis of the recovered mutants showed a TDBP-specific change in mutation spectrum in kidney, which was not observed in liver and stomach. In kidney, a dose-dependent decrease in G:C → A:T transitions, including at 5′-CpG-3′ sites, was observed. This was accompanied by an increase in the loss of single G:C base pairs from approximately 3% to 15%. These results illustrate both the sensitivity and specificity of the lacl transgenic system in the analysis of tissue-specific mutation. This study also reinforces the importance of examining mutational spectra when mutant induction levels are low. © 1996 Wiley-Liss, Inc.